Sjgren's syndrome is a chronic, rheumatic, autoimmune disease that is characterized by a lymphocytic infiltrate of the exocrine glands as well as autoantibodies in the serum (anti-Ro/La or anti-SSA/SSB). Salivary and lacrimal gland dysfunction leads to severe dry eyes and dry mouth (sicca) in almost all patients, while some also have systemic (extra-glandular) manifestations that can involve the skin, lungs, kidneys, peripheral nervous system, muscles, CNS or joints. There is no known effective disease-modifying therapy, so treatment is symptomatic. Pathogenesis of the disease is poorly understood but involves a genetic risk as well as environmental factors. Epstein Barr virus (EBV), a near ubiquitous human infection, has been implicated in Sjgren's syndrome by several lines of evidence but a mechanism by which EBV might mediate pathogenesis has not been demonstrated. A recent study found that Epstein Barr nuclear antigen 2 (EBNA2), a viral transcription factor, preferentially binds genetics intervals containing a risk gene for systemic lupus erythematosus. This disease is highly related to Sjgren's, including a substantial overlap of the respective genetic associations. Binding to these lupus genomic areas was stronger when the interval contained the risk allele of the associated single nucleotide polymorphism. Thus, our central hypothesis is that EBNA2 expression and its binding of gene promoter regions containing Sjgren's-associated single nucleotide polymorphisms is a critical factor in the pathogenesis of Sjgren's syndrome. We will test this hypothesis by determining whether EBNA2 tends to bind genetic intervals with Sjgren's risk genes by use of novel search and analysis strategies. In addition we will determine whether EBNA2 is expressed more commonly in Sjgren's salivary glands compared to glands from subjects without Sjgren's syndrome. The second set of studies will use single cell transcriptome profiling from salivary gland frozen sections. This approach will find changes in gene expression associated with EBNA2 expression. Thus, we will leverage our repository of more than 1000 minor salivary gland biopsy specimens tied to extensive clinical and laboratory data for this project. This project also takes advantage of the opportunity afforded when studying Sjgren's to easily access the involved tissue; namely, salivary gland.